Continuous rhythmic breathing movements are essential for respiratory homeostasis. The magnitude and rate of inspiratory efforts are precisely regulated to maintain arterial oxygen and carbon dioxide tensions and pH within narrow limits despite variations in metabolic requirements. This regulation depends upon afferent input to the central nervous system from several sensory systems including the slowly adapting pulmonary stretch receptors and peripheral chemoreceptors. This proposal seeks to characterize the physiology and anatomy of central afferent pathways controlling breathing. Specifically, the goal of this research is to identify the neural pathways mediating the respiratory reflex responses to activation of slowly adapting pulmonary stretch receptors and the central neural mechanisms by which peripheral chemoreceptor afferent input modifies these responses. To attain this goal, we propose a series of electrophysiological, pharmacological, and neuroanatomical studies. To identify these pathways, small injections of excitatory amino acids will be made into the brainstem and the effects on respiratory motor output determined. Sites where chemical injection produces changes in motor output resembling changes in response to pulmonary stretch receptor activation will be identified as potential sites of pulmonary stretch receptor processing. Neurons within these regions will be tested for pulmonary stretch receptor input by using standard manipulations of lung volume, and for peripheral chemoreceptor input by using cyanide injections or inhalation of hypoxic gas mixtures. Once neurons receiving stretch receptor input are located, their role in generating the reflex responses to pulmonary stretch receptor activation will be determined by interrupting their synaptic input with local injections of cobalt and determining the effect on the reflex response. The axonal projections of neurons found to be involved in stretch receptor-mediated reflexes will be identified using neuroanatomical tracers and electrophysiological mapping. Whether neurons receiving the identified projections are components of the pulmonary stretch receptor reflex pathway will be determined by: 1) the response to injection of excitatory amino acids into the labeled sites, and 2) the effect of cobalt injection on the reflex response to physiological activation of the stretch receptors. Specific synaptic connections between the neurons within these different regions will be established using unit- unit cross-correlation analysis. These studies will provide a mechanistic characterization of a primary reflex regulating the depth of inspiration and rate of breathing. The findings will aid in the development of prophylaxis and treatment of respiratory diseases such as central alveolar hypoventilation.